In a first aspect, the invention relates to a process for preparing chiral diol sulfones, which are advanced intermediates used in preparing statins, a class of compounds useful as HMG CoA reductase inhibitors.
A method for preparing chiral diol sulfones is described in WO 2002/098854 and WO 2001/096311 wherein a sulfone is prepared from an alcohol, more in particular tert-butyl 2-(4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate known as “Kaneka alcohol”. The preparation of such an alcohol is described in EP 1024139.
The synthesis of the sulfone in the prior art has a disadvantage, in that trifluoromethanesulfonic anhydride or another sulfonic acid derived activating agent is used to activate the alcohol function to an extent that a nucleophilic attack with a thiol is possible. Trifluoromethanesulfonic anhydride is an extremely hazardous and expensive component, which causes costly work-up procedures due to environmentally problematic waste streams. In WO 2010/140765 this problem has been addressed by direct reaction of a halomethyl derivative of a very specific and highly sterically hindered 2-methyl-1-phenylpropan-2-yl ester. Although this represents a first example of a direct nucleophilic attack by a thiol compound on a halide, the bulkiness of the ester group inherently also prevents the side reaction of unwanted substitution of the ester moiety leading to unwanted thio-ester.
It is an object of the present invention to provide a process, in which not only the use of an activating agent like trifluoromethanesulfonic anhydride is omitted but which is also applicable to esters of sterically unhindered and/or small alcohols such as butyl esters, ethyl esters, methyl esters and propyl esters.